Hepatitis C virus (HCV) is a single stranded positive RNA virus belonging to the flaviviridae family. Infection by HCV is the main cause of chronic liver disease with over 170 million people infected worldwide. See, for example, Rosenberg, S. J. Mo. Biol. (2001) 313: 451 and Giannini, C.; Brechot, C. Cell Death Differ. (2003) 10: S27. Over three million Americans are infected by the HCV virus, which is particularly lethal for AIDS patients (http://www.cdc.gov/hepatitis/Statistics.htm#section1), of whom increasing numbers are co-infected with HIV and HCV (McGovern, B. H. J. Acquir. Immune Defic. Syndr. (2007) 45: S47). Nearly 40,000 new cases of HCV are reported yearly in this country, 20% of whom will develop liver cirrhosis, and up to 2.5% of these patients will develop hepatocellular-carcinoma. There is no vaccine for HCV, and the only treatment, a combination of interferon-α and ribavirin, is successful in less than half of the patients. See for example, Simmonds, P. J. J. Gen. Virol. (2004) 85: 3173 and Cristina, J.; del Pilar Moreno, M.; Moratorio, G. Virus Res. (2007) 127: 185. Until recently, the main efforts to develop novel HCV inhibitors has been on the viral protease and polymerase enzymes, but escape mutants have already been reported. See Courcameck, et al., Antivir. Ther. (2006) 11: 847 and DeFrancesco, R.; Caffi, A. Adv. Drug Delivery Rev. (2007) 59: 1242.
The HCV RNA enodes a polyprotein which is co- and post-translationally processed into ten individual proteins by host cell signal peptidases and viral peptidases (Bartenschlager, R.; Lohmann, V. J. Gen. Virol. (2000) 81: 1631). All ten proteins are essential for viral infectivity. One of these proteins, known as “core”, is a 191 amino acid capsid protein which is required for viral assembly within the host cell following post-translational processing (Santolini, E.; Migliaccio, G.; La Monica, N. J. Virol. (1994) 68: 3631). Core is the most conserved of all HCV proteins, across the 6 major genotypes, and that it is the least variable of the ten HCV proteins in variant viruses emerging constantly in patients. As such, core has emerged as a viable target for drug therapy against HCV (Strosberg, A. D.; Kota, S.; Takahashi, V.; Snyder, J. K.; Mousseau, G. Viruses (2010) 2: 1734).